Genetic Variant RIT1:p.Glu81Gly (chr1-155904498-T-C) – ACMG Classification: Pathogenic (16 pts)

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_001256821.2(RIT1):c.293A>G(p.Glu98Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E98Q) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

RIT1
NM_001256821.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16

Conservation

PhyloP100: 6.52

Publications

15 publications found

Variant links:

Genes affected

RIT1 (HGNC:10023): (Ras like without CAAX 1) This gene encodes a member of a subfamily of Ras-related GTPases. The encoded protein is involved in regulating p38 MAPK-dependent signaling cascades related to cellular stress. This protein also cooperates with nerve growth factor to promote neuronal development and regeneration. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Feb 2012]

RIT1 Gene-Disease associations (from GenCC):

Noonan syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
Noonan syndrome 8
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Genomics England PanelApp

RIT1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PM1

In a hotspot region, there are 18 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001256821.2

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-155904499-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 183404.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.92

PP5

Variant 1-155904498-T-C is Pathogenic according to our data. Variant chr1-155904498-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 183405.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256821.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RIT1	NM_006912.6	MANE Select	c.242A>G	p.Glu81Gly	missense	Exon 5 of 6	NP_008843.1
RIT1	NM_001256821.2		c.293A>G	p.Glu98Gly	missense	Exon 5 of 6	NP_001243750.1
RIT1	NM_001256820.2		c.134A>G	p.Glu45Gly	missense	Exon 4 of 5	NP_001243749.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RIT1	ENST00000368323.8	TSL:1 MANE Select	c.242A>G	p.Glu81Gly	missense	Exon 5 of 6	ENSP00000357306.3
RIT1	ENST00000609492.1	TSL:1	c.242A>G	p.Glu81Gly	missense	Exon 4 of 5	ENSP00000476612.1
RIT1	ENST00000368322.7	TSL:3	c.293A>G	p.Glu98Gly	missense	Exon 5 of 6	ENSP00000357305.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000426

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Noonan syndrome 8 (7)

Noonan syndrome (2)

not provided (2)

Inborn genetic diseases (1)

Noonan syndrome and Noonan-related syndrome (1)

not specified (1)

RASopathy (1)

RIT1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.77

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.48

MetaRNN

Pathogenic

0.92

MetaSVM

Uncertain

0.50

MutationAssessor

Pathogenic

3.0

PhyloP100

6.5

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-6.3

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0080

Polyphen

1.0

Vest4

0.95

MutPred

0.68

Loss of stability (P = 0.0698)

MVP

0.91

MPC

2.0

ClinPred

0.99

GERP RS

5.8

Varity_R

0.90

gMVP

0.93

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over